We have previously demonstrated that adult HSC produce circulating endothelial progenitor cells (EPC) in response to ischemic injury. We utilize a model of neovascularization in the murine retina that results in high levels of HSC-derived contribution in the new vessels. Our preliminary data and that from other labs suggest that the degree of ischemic damage dictates the overall level of HSC contribution to new vessels. Recent work also suggests that new vessel formation results from an interplay between HSC-derived EPC and circulating endothelial cells (EC) derived from existing vessels. In this renewal application we will extend of previous work to examine what differing roles of HSC-derived EPC and vessel-derived EC in new vessel generation and existing vessel repair. We will also test potential mechanisms to promote EPC driven vessel formation/repair and the role hypoxia and hypoxia regulated factors in HSC production of EPC. The purpose of this proposal is to define the role of hematopoietic cells in new blood vessel formation and damaged vessel repair. Preclinical data for the prevention of proliferative retinopathy and cardiovascular disease will lay the groundwork for phase I clinical trails. PUBLID HEALTH RELEVANCE: The purpose of this proposal is to define the role of hematopoietic cells in new blood vessel formation and damaged vessel repair. Preclinical data for the prevention of proliferative retinopathy and cardiovascular disease will lay the groundwork for phase I clinical trails.